T cells play an important role in controlling tumor growth and mediating tumor regression. To understand the molecular basis of T cell-mediated antitumor immunity, a number of tumor antigens recognized by CD8+ T cells have been identified in melanoma as well as in other types of cancers (1-3). These studies have led to several clinical trials using peptides derived from the molecularly defined tumor antigens (4-7). Although the clinical trial using a modified peptide derived from gp100 provided some evidence of therapeutic efficacy for the treatment of patients with metastatic melanoma (4), these studies mainly focused on the use of CD8+ T cells. Increasing evidence from both human and animal studies has indicated that optimal cancer vaccines require the participation of both CD4+ and CD8+ T cells (8, 9). Moreover, tumor-specific CD4+ T cells are required for generating protective immunity against MHC class II-negative tumor cells (10, 11). Identification of such antigens is thus important for the development of cancer vaccines as well as for our understanding of the mechanism by which CD4+ T cells regulate host immune responses.
Thus far, only a limited number of MHC class II-restricted tumor antigens have been identified. Several known MHC class I-restricted tumor antigens such as tyrosinase, gp100 and MAGE-3 were demonstrated to contain MHC class II-restricted epitopes recognized by CD4+ T cells (12-15). Recently, a genetic approach was developed to identify unknown MHC class II-restricted tumor antigens by using tumor-specific CD4+ T cells (16). This has led to the identification of several mutated tumor antigens including CDC27, TPI and LDFP (16, 17). Among them, TPI is a mutated antigen that was independently identified by a biochemical approach (18).
The NY-ESO-1 gene was previously identified by antibody screening (19), and was recently identified as an MHC class I-restricted tumor antigen as well (20, 21). High titers of antibodies against NY-ESO-1 were also detected from patients with cancer (22). The NY-ESO-1 cDNA encoded two gene products from two overlapping open reading frames (20). Because of its strict tumor-specific expression pattern with the exception of expression in normal testis as well as its high frequency of expression in many tumors including melanoma, breast, prostate, lung and other cancers (18, 20, 23), NY-ESO-1 is potentially an important immune target for the development of immunotherapies for a variety of cancer types (24).
Although both CTL and antibody immune responses against NY-ESO-1 were demonstrated in patients with cancer, no MHC class II-restricted T cell epitopes in the NY-ESO-1 protein have been reported.
The present invention is the identification and isolation of novel MHC class II restricted T cell epitopes from NY-ESO-1 which are recognized by CD4+ T cells. The cancer epitopes of the invention are useful as an immunogen and vaccine to inhibit or prevent cancer in a mammal and as a diagnostic agent to detect cancer or precancer.